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Non-union of bone following fracture is an orthopaedic condition with a high morbidity and clinical burden. Despite its estimated global prevalence of nine million annually, the limit of bone regeneration therapy still results in patients living with pain, a reduced quality of life and associated psychological, social and financial repercussions. This review provides an overview of the current epidemiological and aetiological data, and highlights where the clinical challenges in treating non-union lie. Current treatment strategies are discussed as well as promising future research foci. Development in biotechnologies to treat non-union provides exciting scope for more effective treatment for this debilitating condition.
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A common polymorphism in the 3' untranslated region of the stromal cell-derived factor 1 (also called pre-B-cell-stimulating factor) beta gene transcript, termed SDF1-3'A, has been associated with an increased risk of non-Hodgkin's lymphoma (NHL) in HIV-1-infected, but not in uninfected, individuals. Because the gene variation is located within the 3' untranslated region, the SDF1-3'A may influence the abundance of SDF-1 mRNA, possibly up-regulating the chemokine expression especially in the presence of HIV-1. In the current study, we investigated the levels of SDF-1 mRNA in peripheral blood mononuclear cells and HIV-1 viral load in 84 HIV-1-infected children (0.7 to 18 years of age; median, 5.8), including 12 children who developed NHL during their illnesses (AIDS-NHL group; 8 with SDF1-3'A, 4 with SDF1-wild-type). High level SDF-1 expression was observed in 15 of 34 children with SDF1-3'A as compared with 10 of 50 with wild type (P < 0.03). More notably, the children with AIDS-NHL had significantly elevated levels of SDF-1 mRNA in peripheral blood mononuclear cells, obtained at the time of presentation in 10 children and 8.5 to 19.4 months before (median, 15 months) in 7 children, as compared with the children in the non-NHL group (P < 0.00001). The amounts of cell-associated HIV-1 DNA and singly spliced HIV-1 mRNA were significantly greater in children with AIDS-NHL than those with non-NHL AIDS (P = 0.0052 and 0.011, respectively; stratified by antiretroviral treatment regimen), whereas their serum HIV-1 RNA levels were comparable. Overexpression of SDF-1 and aberrant HIV-1 expression in circulating lymphocytes appear to be linked to the development of AIDS-lymphoma. Additional studies are required to determine whether excessive SDF-1, together with virally encoded factors, is directly involved in the pathogenesis of AIDS-lymphoma.
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Quimiocinas CXC/genética , Infecciones por VIH/sangre , VIH-1 , Linfoma Relacionado con SIDA/sangre , Linfoma no Hodgkin/sangre , ARN Mensajero/sangre , Adolescente , Quimiocina CXCL12 , Quimiocinas CXC/biosíntesis , Niño , Preescolar , ADN Viral/sangre , Femenino , Infecciones por VIH/complicaciones , Infecciones por VIH/genética , Herpesvirus Humano 4/genética , Humanos , Lactante , Tejido Linfoide/metabolismo , Linfoma Relacionado con SIDA/genética , Linfoma no Hodgkin/genética , Linfoma no Hodgkin/virología , Masculino , ARN Mensajero/metabolismo , Carga ViralRESUMEN
BACKGROUND: Early treatment for Crohn's disease (CD) with immunomodulators and/or anti-TNF agents improves outcomes in comparison to a slower 'step up' algorithm. However, there remains a limited ability to identify those who would benefit most from early intensive therapy. AIM: To develop a validated, individualised, web-based tool for patients and clinicians to visualise individualised risks for developing Crohn's disease complications. METHODS: A well-characterised cohort of adult patients with CD was analysed. Available data included: demographics; clinical characteristics; serologic immune responses; NOD2 status; time from diagnosis to complication; and medication exposure. Cox proportional analyses were performed to model the probability of developing a CD complication over time. The Cox model was validated externally in two independent CD cohorts. Using system dynamics analysis (SDA), these results were transformed into a simple graphical web-based display to show patients their individualised probability of developing a complication over a 3-year period. RESULTS: Two hundered and forty three CD patients were included in the final model of which 142 experienced a complication. Significant variables in the multivariate Cox model included small bowel disease (HR 2.12, CI 1.05-4.29), left colonic disease (HR 0.73, CI 0.49-1.09), perianal disease (HR 4.12, CI 1.01-16.88), ASCA (HR 1.35, CI 1.16-1.58), Cbir (HR 1.29, CI 1.07-1.55), ANCA (HR 0.77, CI 0.62-0.95), and the NOD2 frameshift mutation/SNP13 (HR 2.13, CI 1.33-3.40). The Harrell's C (concordance index for predictive accuracy of the model) = 0.73. When applied to the two external validation cohorts (adult n = 109, pediatric n = 392), the concordance index was 0.73 and 0.75, respectively, for adult and pediatric patients. CONCLUSIONS: A validated, web-based tool has been developed to display an individualised predicted outcome for adult patients with Crohn's disease based on clinical, serologic and genetic variables. This tool can be used to help providers and patients make personalised decisions about treatment options.
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Enfermedad de Crohn/tratamiento farmacológico , Factores Inmunológicos/uso terapéutico , Internet , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Adolescente , Adulto , Anciano , Femenino , Humanos , Masculino , Estudios Prospectivos , Estudios Retrospectivos , Riesgo , Adulto JovenRESUMEN
OBJECTIVE: To determine the influences on pediatric AIDS of a heterozygous 32 base pair deletion in the CC-chemokine receptor 5 gene (CCR5 wt/Delta 32) and a common polymorphism in the 3' untranslated region of stromal cell-derived factor-1 beta gene transcript (SDF1-3'A). DESIGN: The rate of HIV-1 disease progression and viral burden were compared according to the CCR5 and SDF-1 genotypes in 127 (58 Caucasians, 60 African-Americans and nine Hispanics) perinatally HIV-1-infected children. RESULTS: Regardless of ethnic background, the CCR5 wt/Delta 32 genotype was associated with a delayed onset of AIDS-defining infectious complications during the first 5 years of infection [relative hazard (RH) = 0.22; 95% confidence interval (CI), 0.012--1.02; P = 0.053]. Similarly, CCR5 wt/Delta 32 conferred an early protection against severe immune suppression and HIV-1 encephalopathy, but only in those without SDF1-3'A (RH = 0; 95% CI, 0--0.70; P = 0.020, and RH = 0; 95% CI, 0--0.71; P = 0.021, respectively). When examined before 5 years of age (n = 81), the children with CCR5 wt/Delta 32 had significantly lower levels of cell-associated HIV-1 DNA than wild-type homozygotes (P = 0.016, adjusted by race), while SDF1-3'A carriers had relatively higher levels (P = 0.047, adjusted by race). Although the disease-retarding effect of CCR5 wt/Delta 32 subsequently disappeared, time to death was still significantly delayed in the CCR5 Delta 32 heterozygotes without SDF1-3'A (RH = 0; 95% CI, 0--0.53; P = 0.008). CONCLUSION: In pediatric AIDS, the protective effect of CCR5 wt/Delta 32 is more pronounced in early years of infection and appears to be abrogated by the SDF1-3'A genotype.
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Quimiocinas CXC/genética , Infecciones por VIH/genética , VIH-1 , Receptores CCR5/genética , Adolescente , Alelos , Secuencia de Bases , Quimiocina CXCL12 , Niño , Preescolar , ADN Viral/sangre , Progresión de la Enfermedad , Genotipo , Infecciones por VIH/epidemiología , Infecciones por VIH/patología , Heterocigoto , Humanos , Lactante , Modelos de Riesgos Proporcionales , Eliminación de Secuencia , Análisis de SupervivenciaRESUMEN
A prospective series of 110 alleged rape victims from July through November 1974 at Denver General Hospital is presented. The victims and assailants are characterized. The laboratory established proof of recent coitus in 68%. Four-fifths of the victims presented within 12 hours of the alleged incident. The analysis of ABO vaginal antigens appears to be promising for assailant identification. Follow-up by appointment in this group was successful in only 5%. Only a minority of cases led to arrest and criminal proceedings. Suggestions are made for alternative approaches to victims based on new developments in forensic laboratory procedures.
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Medicina Legal , Violación , Sistema del Grupo Sanguíneo ABO , Adolescente , Adulto , Anciano , Niño , Femenino , Estudios de Seguimiento , Humanos , Persona de Mediana Edad , Examen Físico , Frotis VaginalRESUMEN
The amount of human immunodeficiency virus (HIV) type 1 RNA and the presence of a codon 215 mutation indicative of zidovudine resistance were evaluated in cerebrospinal fluid (CSF) and plasma obtained from HIV-1-infected children. The level of HIV-1 RNA in CSF was highest in children with severe encephalopathy (n = 25; median, 430 copies/mL; range, 0-2.2 x 10(5) copies/mL) followed by the moderately encephalopathic (n = 7; median, 330; range, 0-1130) and nonencephalopathic groups (n = 9; median, 0; range, 0-566) (P = .007). There was no correlation between CSF and plasma HIV-1 RNA levels. Five of 7 children with the codon 215 mutation in CSF had a progression of encephalopathy, while all 8 children with wild type codon 215 had improved or stable disease during zidovudine treatment (P = .007). These findings suggest that increased viral replication and emergence of drug-resistant HIV-1 variants within the central nervous system may play a role in progression of HIV encephalopathy.
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Complejo SIDA Demencia/tratamiento farmacológico , Complejo SIDA Demencia/virología , Fármacos Anti-VIH/uso terapéutico , Farmacorresistencia Microbiana/genética , Infecciones por VIH/tratamiento farmacológico , Infecciones por VIH/virología , VIH-1/crecimiento & desarrollo , VIH-1/genética , ARN Viral/análisis , Zidovudina/uso terapéutico , Complejo SIDA Demencia/sangre , Complejo SIDA Demencia/líquido cefalorraquídeo , Recuento de Linfocito CD4 , Niño , Preescolar , Progresión de la Enfermedad , Estudios de Seguimiento , Genes pol , Proteína p24 del Núcleo del VIH/análisis , Infecciones por VIH/sangre , Infecciones por VIH/líquido cefalorraquídeo , VIH-1/patogenicidad , Humanos , Lactante , Mutación Puntual , Reacción en Cadena de la PolimerasaRESUMEN
Levels of human immunodeficiency virus type 1 (HIV-1) DNA and quinolinic acid were examined in areas of the central nervous system (CNS) and lymphoid organs (LN) from 5 AIDS patients with no clinically apparent CNS compromise (group I), 7 with CNS opportunistic diseases (group II), and 8 with HIV encephalopathy (group III). The brains from patients with HIV encephalopathy not only contained higher levels of HIV-1 DNA (cerebrum, P < .01; cerebellum, P < .05) as assessed by quantitative polymerase chain reaction but also showed a higher rate of viral pol region mutations suggestive of zidovudine or didanosine resistance than brains from patients in group I or II (P < .01). CNS quinolinic acid concentrations were significantly higher in group II and III patients than in group I (P = .03), even though quinolinic acid levels in LN were comparable among the 3 groups. These data suggest that CNS inflammatory changes associated with HIV encephalopathy may be triggered by a local productive HIV-1 infection within the CNS.
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Complejo SIDA Demencia/virología , Química Encefálica , Encéfalo/virología , ADN Viral/análisis , VIH-1/aislamiento & purificación , Ácido Quinolínico/análisis , Factor de Necrosis Tumoral alfa/análisis , Complejo SIDA Demencia/tratamiento farmacológico , Complejo SIDA Demencia/patología , Infecciones Oportunistas Relacionadas con el SIDA/patología , Infecciones Oportunistas Relacionadas con el SIDA/virología , Adolescente , Adulto , Secuencia de Bases , Células Cultivadas , Cerebelo/virología , Niño , Preescolar , Cartilla de ADN , Didanosina/uso terapéutico , Genes pol , VIH-1/genética , Humanos , Lactante , Macrófagos/virología , Persona de Mediana Edad , Datos de Secuencia Molecular , Mutación , Especificidad de Órganos , Reacción en Cadena de la Polimerasa/métodos , Zidovudina/uso terapéuticoRESUMEN
Myosin heavy chain (MyHC) is the major contractile protein of muscle. We report the first complete cosmid cloning and definitive physical map of the tandemly linked human skeletal MyHC genes at 17p13.1. The map provides new information on the order, size, and relative spacing of the genes. and it resolves uncertainties about the two fastest twitch isoforms. The physical order of the genes is demonstrated to contrast with the temporal order of their developmental expression. Furthermore, nucleotide sequence comparisons allow an approximation of the relative timing of five ancestral duplications that created distinct genes for the six isoforms. A firm foundation is provided for molecular analysis in patients with suspected primary skeletal myosinopathies and for detailed modelling of the hypervariable surface loops which dictate myosin's kinetic properties.